Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?
August 12, 2021
August 12, 2021
There is an urgent need to find ways to help patients who do not have a persistent response to immune ‘checkpoint’ therapy for MCC. This review details surprising new findings from multiple labs that suggest such patients might benefit from blocking the ‘sensor’ a cancer cell uses to verify it has fully copied its DNA prior to dividing into two cells. We have known for over 20 years that blocking this sensor of DNA replication could selectively kill cancer cells (by tricking them to divide before finishing copying the 7 feet of DNA in every cell). What is exciting is that it appears that these newly available drugs kill cancer cells in a way that helps the immune system to recognize and destroy cancer cells elsewhere in the body. We are planning a clinical trial to see if this can indeed help MCC patients who do not persistently benefit from current immune therapy.
Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered clinical trials. Surprisingly, preclinical studies have now indicated that DDRi may stimulate anti-tumor immunity to augment immunotherapy. The mechanisms governing how DDRi could promote anti-tumor immunity are not well understood; however, early evidence suggests that they can potentiate immunogenic cell death to recruit and activate antigen-presenting cells to prime an adaptive immune response. Merkel cell carcinoma (MCC) is well suited to test these concepts. It is inherently immunogenic as ~50% of patients with advanced MCC persistently benefit from immunotherapy, making MCC one of the most responsive solid tumors. As is typical of neuroendocrine cancers, dysfunction of p53 and Rb with upregulation of Myc leads to the very rapid growth of MCC. This suggests high replication stress and susceptibility to DDRi and DNA-damaging agents. Indeed, MCC tumors are particularly radiosensitive. Given its inherent immunogenicity, cell cycle checkpoint deficiencies and sensitivity to DNA damage, MCC may be ideal for testing whether targeting the intersection of the DDR checkpoint and the immune checkpoint could help patients with immunotherapy-refractory cancers.